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1.
Genome Res ; 2022 Jan 21.
Article in English | MEDLINE | ID: covidwho-1642462

ABSTRACT

The pathogenesis of COVID-19 is still elusive, which impedes disease progression prediction, differential diagnosis, and targeted therapy. Plasma cell-free RNAs (cfRNAs) carry unique information from human tissue and thus could point to resourceful solutions for pathogenesis and host-pathogen interactions. Here, we performed a comparative analysis of cfRNA profiles between COVID-19 patients and healthy donors using serial plasma. Analyses of the cfRNA landscape, potential gene regulatory mechanisms, dynamic changes in tRNA pools upon infection, and microbial communities were performed. A total of 380 cfRNA molecules were up-regulated in all COVID-19 patients, of which seven could serve as potential biomarkers (AUC > 0.85) with great sensitivity and specificity. Antiviral (NFKB1A, IFITM3, and IFI27) and neutrophil activation (S100A8, CD68, and CD63)-related genes exhibited decreased expression levels during treatment in COVID-19 patients, which is in accordance with the dynamically enhanced inflammatory response in COVID-19 patients. Noncoding RNAs, including some microRNAs (let 7 family) and long noncoding RNAs (GJA9-MYCBP) targeting interleukin (IL6/IL6R), were differentially expressed between COVID-19 patients and healthy donors, which accounts for the potential core mechanism of cytokine storm syndromes; the tRNA pools change significantly between the COVID-19 and healthy group, leading to the accumulation of SARS-CoV-2 biased codons, which facilitate SARS-CoV-2 replication. Finally, several pneumonia-related microorganisms were detected in the plasma of COVID-19 patients, raising the possibility of simultaneously monitoring immune response regulation and microbial communities using cfRNA analysis. This study fills the knowledge gap in the plasma cfRNA landscape of COVID-19 patients and offers insight into the potential mechanisms of cfRNAs to explain COVID-19 pathogenesis.

3.
Lancet Rheumatol ; 2021 Nov 15.
Article in English | MEDLINE | ID: covidwho-1591231

ABSTRACT

Background: Many individuals take long-term immunosuppressive medications. We evaluated whether these individuals have worse outcomes when hospitalised with COVID-19 compared with non-immunosuppressed individuals. Methods: We conducted a retrospective cohort study using data from the National COVID Cohort Collaborative (N3C), the largest longitudinal electronic health record repository of patients in hospital with confirmed or suspected COVID-19 in the USA, between Jan 1, 2020, and June 11, 2021, within 42 health systems. We compared adults with immunosuppressive medications used before admission to adults without long-term immunosuppression. We considered immunosuppression overall, as well as by 15 classes of medication and three broad indications for immunosuppressive medicines. We used Fine and Gray's proportional subdistribution hazards models to estimate the hazard ratio (HR) for the risk of invasive mechanical ventilation, with the competing risk of death. We used Cox proportional hazards models to estimate HRs for in-hospital death. Models were adjusted using doubly robust propensity score methodology. Findings: Among 231 830 potentially eligible adults in the N3C repository who were admitted to hospital with confirmed or suspected COVID-19 during the study period, 222 575 met the inclusion criteria (mean age 59 years [SD 19]; 111 269 [50%] male). The most common comorbidities were diabetes (23%), pulmonary disease (17%), and renal disease (13%). 16 494 (7%) patients had long-term immunosuppression with medications for diverse conditions, including rheumatological disease (33%), solid organ transplant (26%), or cancer (22%). In the propensity score matched cohort (including 12 841 immunosuppressed patients and 29 386 non-immunosuppressed patients), immunosuppression was associated with a reduced risk of invasive ventilation (HR 0·89, 95% CI 0·83-0·96) and there was no overall association between long-term immunosuppression and the risk of in-hospital death. None of the 15 medication classes examined were associated with an increased risk of invasive mechanical ventilation. Although there was no statistically significant association between most drugs and in-hospital death, increases were found with rituximab for rheumatological disease (1·72, 1·10-2·69) and for cancer (2·57, 1·86-3·56). Results were generally consistent across subgroup analyses that considered race and ethnicity or sex, as well as across sensitivity analyses that varied exposure, covariate, and outcome definitions. Interpretation: Among this cohort, with the exception of rituximab, there was no increased risk of mechanical ventilation or in-hospital death for the rheumatological, antineoplastic, or antimetabolite therapies examined. Funding: None.

4.
JAMA Intern Med ; 2021 Dec 28.
Article in English | MEDLINE | ID: covidwho-1598451

ABSTRACT

Importance: Persons with immune dysfunction have a higher risk for severe COVID-19 outcomes. However, these patients were largely excluded from SARS-CoV-2 vaccine clinical trials, creating a large evidence gap. Objective: To identify the incidence rate and incidence rate ratio (IRR) for COVID-19 breakthrough infection after SARS-CoV-2 vaccination among persons with or without immune dysfunction. Design, Setting, and Participants: This retrospective cohort study analyzed data from the National COVID Cohort Collaborative (N3C), a partnership that developed a secure, centralized electronic medical record-based repository of COVID-19 clinical data from academic medical centers across the US. Persons who received at least 1 dose of a SARS-CoV-2 vaccine between December 10, 2020, and September 16, 2021, were included in the sample. Main Outcomes and Measures: Vaccination, COVID-19 diagnosis, immune dysfunction diagnoses (ie, HIV infection, multiple sclerosis, rheumatoid arthritis, solid organ transplant, and bone marrow transplantation), other comorbid conditions, and demographic data were accessed through the N3C Data Enclave. Breakthrough infection was defined as a COVID-19 infection that was contracted on or after the 14th day of vaccination, and the risk after full or partial vaccination was assessed for patients with or without immune dysfunction using Poisson regression with robust SEs. Poisson regression models were controlled for a study period (before or after [pre- or post-Delta variant] June 20, 2021), full vaccination status, COVID-19 infection before vaccination, demographic characteristics, geographic location, and comorbidity burden. Results: A total of 664 722 patients in the N3C sample were included. These patients had a median (IQR) age of 51 (34-66) years and were predominantly women (n = 378 307 [56.9%]). Overall, the incidence rate for COVID-19 breakthrough infection was 5.0 per 1000 person-months among fully vaccinated persons but was higher after the Delta variant became the dominant SARS-CoV-2 strain (incidence rate before vs after June 20, 2021, 2.2 [95% CI, 2.2-2.2] vs 7.3 [95% CI, 7.3-7.4] per 1000 person-months). Compared with partial vaccination, full vaccination was associated with a 28% reduced risk for breakthrough infection (adjusted IRR [AIRR], 0.72; 95% CI, 0.68-0.76). People with a breakthrough infection after full vaccination were more likely to be older and women. People with HIV infection (AIRR, 1.33; 95% CI, 1.18-1.49), rheumatoid arthritis (AIRR, 1.20; 95% CI, 1.09-1.32), and solid organ transplant (AIRR, 2.16; 95% CI, 1.96-2.38) had a higher rate of breakthrough infection. Conclusions and Relevance: This cohort study found that full vaccination was associated with reduced risk of COVID-19 breakthrough infection, regardless of the immune status of patients. Despite full vaccination, persons with immune dysfunction had substantially higher risk for COVID-19 breakthrough infection than those without such a condition. For persons with immune dysfunction, continued use of nonpharmaceutical interventions (eg, mask wearing) and alternative vaccine strategies (eg, additional doses or immunogenicity testing) are recommended even after full vaccination.

5.
Signal Transduct Target Ther ; 6(1): 428, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1585884

ABSTRACT

SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. In this study, we showed that SARS-CoV-2-triggered MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation altered various signaling pathways in alveolar epithelial cells, particularly, the induction of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments.


Subject(s)
COVID-19/metabolism , Cell Degranulation , Lung Injury/metabolism , Mast Cells/metabolism , Pulmonary Alveoli/metabolism , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/genetics , Cell Line, Tumor , Female , Humans , Lung Injury/genetics , Lung Injury/virology , Macaca mulatta , Male , Mice, Inbred BALB C , Mice, Transgenic , Pulmonary Alveoli/virology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
6.
Cell Discov ; 7(1): 65, 2021 Aug 12.
Article in English | MEDLINE | ID: covidwho-1569241

ABSTRACT

The current COVID-19 pandemic, caused by SARS-CoV-2, poses a serious public health threat. Effective therapeutic and prophylactic treatments are urgently needed. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for SARS-CoV-2, which binds to the receptor binding domain (RBD) of SARS-CoV-2 spike protein. Here, we developed recombinant human ACE2-Fc fusion protein (hACE2-Fc) and a hACE2-Fc mutant with reduced catalytic activity. hACE2-Fc and the hACE2-Fc mutant both efficiently blocked entry of SARS-CoV-2, SARS-CoV, and HCoV-NL63 into hACE2-expressing cells and inhibited SARS-CoV-2 S protein-mediated cell-cell fusion. hACE2-Fc also neutralized various SARS-CoV-2 strains with enhanced infectivity including D614G and V367F mutations, as well as the emerging SARS-CoV-2 variants, B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.1 (Kappa), and B.1.617.2 (Delta), demonstrating its potent and broad-spectrum antiviral effects. In addition, hACE2-Fc proteins protected HBE from SARS-CoV-2 infection. Unlike RBD-targeting neutralizing antibodies, hACE2-Fc treatment did not induce the development of escape mutants. Furthermore, both prophylactic and therapeutic hACE2-Fc treatments effectively protected mice from SARS-CoV-2 infection, as determined by reduced viral replication, weight loss, histological changes, and inflammation in the lungs. The protection provided by hACE2 showed obvious dose-dependent efficacy in vivo. Pharmacokinetic data indicated that hACE2-Fc has a relative long half-life in vivo compared to soluble ACE2, which makes it an excellent candidate for prophylaxis and therapy for COVID-19 as well as for SARS-CoV and HCoV-NL63 infections.

7.
J Appl Dev Psychol ; 78: 101375, 2022.
Article in English | MEDLINE | ID: covidwho-1568498

ABSTRACT

The COVID-19 pandemic and associated government-mandated shutdowns disrupted schooling, socialization, and family life for school-aged children during spring 2020. These disruptions may have contributed to increased child behavior problems. Thus, we examined behavior problems in 247 children aged 7 to 9 years during Ohio's shutdown period. We investigated whether differences in parent-reported child behavior problems were associated with concurrent parent distress during spring 2020 and/or children's social-emotional skills measured via teacher-reports from the previous year (spring 2019). Parent distress significantly predicted behavior problems, such that more distressed parents also reported more child behavior problems. Child pre-pandemic peer social skills also significantly predicted behavior problems, such that more skilled children exhibited fewer behavior problems. There were no interaction effects between parent distress and children's social-emotional skills on child behavior problems. Further research is needed to understand how children's social-emotional skills impact their ability to cope during times of epidemiological crisis.

8.
Front Psychiatry ; 12: 743409, 2021.
Article in English | MEDLINE | ID: covidwho-1560706

ABSTRACT

Background: The novel coronavirus disease 2019 (COVID-19) pandemic has had an adverse impact on the mental health of the general population. This study aimed to investigate the prevalence and correlates of health anxiety (HA) in the general Chinese population to inform psychological interventions in COVID-19-affected areas. Methods: We conducted an online survey of the general population in mainland China between 6 and 17 February 2020 (N = 1,450, 69.79% female; mean age = 37.5 ± 9.1 years). The Whiteley Index-7 (WI-7), COVID-19 knowledge quiz (CKQ), Generalised Anxiety Disorder scale (GAD-7), Patient Health Questionnaire Depression Scale (PHQ-9), and socio-demographic information were surveyed using the Questionnaire-Star program. Results: The prevalence of HA, depression and anxiety were 47.3, 31.3, and 35.7%, respectively. The WI-7 score showed a significant association with age, education level, income, occupation, chronic disease and daily time focused on COVID-19. On binary logistic regression analysis, individuals with masters or higher qualification degree [odds ratio (OR) = 0.632)], older age (OR = 0.981), 2-4 h daily time focused on COVID-19 (OR = 0.684), healthcare workers (OR = 0.749, p = 0.046) and those with more COVID-19 related knowledge (OR = 0.785) showed a significantly negative association with HA. Chronic disease (OR = 1.962), depression (OR = 1.05) and anxiety (OR = 1.228) were significant risk factors for HA. Conclusions: HA was highly prevalent among the general population during the early stages of the COVID-19 outbreak. More than two-fifths of the respondents had obvious HA. Chronic disease, depression and anxiety were risk factors for HA; psychological interventions offered during the pandemic should pay particular attention to these individuals.

9.
Curr Opin Virol ; 52: 102-111, 2021 Dec 11.
Article in English | MEDLINE | ID: covidwho-1559078

ABSTRACT

Human respiratory coronaviruses (HCoVs), including the recently emerged SARS-CoV-2, the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, potentially cause severe lung infections and multiple organ damages, emphasizing the urgent need for antiviral therapeutics and vaccines against HCoVs. Small animal models, especially mice, are ideal tools for deciphering the pathogenesis of HCoV infections as well as virus-induced immune responses, which is critical for antiviral drug development and vaccine design. In this review, we focus on the antiviral innate immune response, antibody response and T cell response in HCoV infected mouse models, and discuss the potential implications for understanding the anti-HCoV immunity and fighting the COVID-19 pandemic.

10.
Preprint in English | Other preprints | ID: ppcovidwho-295289

ABSTRACT

Summary We report the first local transmission of the SARS-CoV-2 Delta variant in mainland China. All 167 infections could be traced back to the first index case. Daily sequential PCR testing of the quarantined subjects indicated that the viral loads of Delta infections, when they first become PCR+, were on average ∼1000 times greater compared to A/B lineage infections during initial epidemic wave in China in early 2020, suggesting potentially faster viral replication and greater infectiousness of Delta during early infection. We performed high-quality sequencing on samples from 126 individuals. Reliable epidemiological data meant that, for 111 transmission events, the donor and recipient cases were known. The estimated transmission bottleneck size was 1-3 virions with most minor intra-host single nucleotide variants (iSNVs) failing to transmit to the recipients. However, transmission heterogeneity of SARS-CoV-2 was also observed. The transmission of minor iSNVs resulted in at least 4 of the 30 substitutions identified in the outbreak, highlighting the contribution of intra-host variants to population level viral diversity during rapid spread. Disease control activities, such as the frequency of population testing, quarantine during pre-symptomatic infection, and level of virus genomic surveillance should be adjusted in order to account for the increasing prevalence of the Delta variant worldwide.

11.
Lancet HIV ; 8(11): e690-e700, 2021 11.
Article in English | MEDLINE | ID: covidwho-1541050

ABSTRACT

BACKGROUND: Evidence of whether people living with HIV are at elevated risk of adverse COVID-19 outcomes is inconclusive. We aimed to investigate this association using the population-based National COVID Cohort Collaborative (N3C) data in the USA. METHODS: We included all adult (aged ≥18 years) COVID-19 cases with any health-care encounter from 54 clinical sites in the USA, with data being deposited into the N3C. The outcomes were COVID-19 disease severity, hospitalisation, and mortality. Encounters in the same health-care system beginning on or after January 1, 2018, were also included to provide information about pre-existing health conditions (eg, comorbidities). Logistic regression models were employed to estimate the association of HIV infection and HIV markers (CD4 cell count, viral load) with hospitalisation, mortality, and clinical severity of COVID-19 (multinomial). The models were initially adjusted for demographic characteristics, then subsequently adjusted for smoking, obesity, and a broad range of comorbidities. Interaction terms were added to assess moderation effects by demographic characteristics. FINDINGS: In the harmonised N3C data release set from Jan 1, 2020, to May 8, 2021, there were 1 436 622 adult COVID-19 cases, of these, 13 170 individuals had HIV infection. A total of 26 130 COVID-19 related deaths occurred, with 445 among people with HIV. After adjusting for all the covariates, people with HIV had higher odds of COVID-19 death (adjusted odds ratio 1·29, 95% CI 1·16-1·44) and hospitalisation (1·20, 1·15-1·26), but lower odds of mild or moderate COVID-19 (0·61, 0·59-0·64) than people without HIV. Interaction terms revealed that the elevated odds were higher among older age groups, male, Black, African American, Hispanic, or Latinx adults. A lower CD4 cell count (<200 cells per µL) was associated with all the adverse COVID-19 outcomes, while viral suppression was only associated with reduced hospitalisation. INTERPRETATION: Given the COVID-19 pandemic's exacerbating effects on health inequities, public health and clinical communities must strengthen services and support to prevent aggravated COVID-19 outcomes among people with HIV, particularly for those with pronounced immunodeficiency. FUNDING: National Center for Advancing Translational Sciences, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA.


Subject(s)
COVID-19/epidemiology , HIV Infections/epidemiology , Pandemics , Adolescent , Adult , Aged , Cohort Studies , Humans , Male , SARS-CoV-2 , United States/epidemiology
12.
J Virol ; : JVI0184221, 2021 Nov 24.
Article in English | MEDLINE | ID: covidwho-1532965

ABSTRACT

Middle East respiratory syndrome coronavirus (MERS-CoV) is a beta coronavirus that emerged in 2012, causing severe pneumonia and renal failure. MERS-CoV encodes five accessory proteins. Some of them have been shown to interfere with host antiviral immune response. However, the roles of protein 8b in innate immunity and viral virulence was rarely studied. Here, we introduced individual MERS-CoV accessory protein genes into the genome of an attenuated murine coronavirus (Mouse hepatitis virus, MHV), respectively and found accessory protein 8b could enhance viral replication in vivo and in vitro, and increase the lethality of infected mice. RNA-seq analysis revealed that protein 8b could significantly inhibit type I interferon production (IFN-I) and innate immune response in mice infected with MHV expressing protein 8b. We also found that MERS-CoV protein 8b could initiate from multiple internal methionine sites and at least three protein variants were identified. Residues 1-23 of protein 8b was demonstrated to be responsible for increased virulence in vivo. In addition, the inhibitory effect on IFN-I of protein 8b might not contribute to its virulence enhancement as aa1-23 deletion did not affect IFN-I production in vitro and in vivo. Next, we also found that protein 8b was localized to the endoplasmic reticulum (ER)/Golgi membrane in infected cells, which was disrupted by C-terminal region aa 88-112 deletion. This study will provide new insight into the pathogenesis of MERS-CoV infection. IMPORTANCE Multiple coronaviruses (CoV) cause severe respiratory infections and become global public health threats such as SARS-CoV, MERS-CoV, and SARS-CoV-2. Each coronavirus contains different numbers of accessory proteins which show high variability among different CoVs. Accessory proteins are demonstrated to play essential roles in pathogenesis of CoVs. MERS-CoV contains 5 accessory proteins (protein 3, 4a, 4b, 5, 8b), and deletion of all four accessory proteins (protein 3, 4a, 4b, 5), significantly affects MERS-CoV replication and pathogenesis. However, whether ORF8b also regulates MERS-CoV infection is unknown. Here, we constructed mouse hepatitis virus (MHV) recombinant virus expressing MERS-CoV protein 8b and demonstrated protein 8b could significantly enhance the virulence of MHV, which is mediated by N-terminal domain of protein 8b. This study will shed light on the understanding of pathogenesis of MERS-CoV infection.

13.
Clin Pediatr (Phila) ; : 99228211058601, 2021 Nov 09.
Article in English | MEDLINE | ID: covidwho-1511594

ABSTRACT

Background. This case-control study aims to investigate the clinical characteristics in pediatric patients with pneumonia infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A, and human adenoviruses (HAdVs). Methods. Hospitalized pediatric patients with pneumonia infected with SARS-CoV-2 at Wuhan Children's Hospital and pneumonia infected with influenza A, and HAdVs at Qilu Children's Hospital were compared. Clinical manifestations, laboratory examinations, and imaging characteristics were analyzed. Results. The proportions of hyperpyrexia (54.3%, 33.9%), cough (100%, 99.2%), wheezing (45.7%, 53.7%), diarrhea (31.4%, 14.9%), and fever (100%, 75.2%) in patients with influenza A and HAdVs were higher than those of patients with SARS-CoV-2 (9.4%, P < .001; 48.5%, P < .001; 0%, P < .001; 8.8%, P = .002; 41.5%, P < .001; respectively). Laboratory examinations revealed the proportions of leukocytosis (37.1%, 52.9%), abnormal rates of neutrophils (40%, 40.5%), and lymphocytosis (42.9%, 65.3%) in influenza A and HAdV pneumonia groups were significantly higher than coronavirus disease 2019 (COVID-19) group (0%, P < .001; 0%, P < .001; 0%, P < .001; respectively). The proportion of elevated procalcitonin (5.7%, 14%) in patients with influenza A and HAdVs was significantly lower than those in patients with SARS-CoV-2 (64%, P < .001). In chest computed tomography, ground-glass opacities near the pleura were more common in patients with COVID-19 than those in patients with influenza A and HAdVs (32.7% vs 0% vs 0%, P < .001). Conclusion. Fever, cough, and wheezing are more common in the influenza A and HAdVs groups, whereas procalcitonin and computed tomography findings are likely to be pronounced in COVID-19 pneumonia. It provides a variety of methods except polymerase chain reaction for differentiating COVID-19 pneumonia from influenza A and HAdVs pneumonia.

14.
Clinical Complementary Medicine and Pharmacology ; : 100009, 2021.
Article in English | ScienceDirect | ID: covidwho-1509628

ABSTRACT

Backgroud : The outbreak of COVID-19 has brought unprecedented perils to human health and raised public health concerns in more than two hundred countries. Safe and effective treatment scheme is needed urgently. Objective : To evaluate the effects of integrated TCM and western medicine treatment scheme on COVID-19. Methods : A single-armed clinical trial was carried out in Hangzhou Xixi Hospital, an affiliated hospital with Zhejiang Chinese Medical University. 102 confirmed cases were screened out from 725 suspected cases and 93 of them were treated with integrated TCM and western medicine treatment scheme. Results : 83 cases were cured, 5 cases deteriorated, and 5 cases withdrew from the study. No deaths were reported. The mean relief time of fever, cough, diarrhea, and fatigue were (4.78±4.61) days, (7.22±4.99) days, (5.28± 3.39) days, and (5.28± 3.39) days, respectively. It took (14.84±5.50) days for SARS-CoV-2 by nucleic acid amplification-based testing to turn negative. Multivariable cox regression analysis revealed that age, BMI, PISCT, BPC, AST, CK, BS, and UPRO were independent risk factors for COVID-19 treatment. Conclusion : Our study suggested that integrated TCM and western medicine treatment scheme was effective for COVID-19.

16.
Antioxidants (Basel) ; 10(10)2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1480546

ABSTRACT

To investigate the effects of tannins (TA) on porcine oocyte in vitro maturation (IVM), different concentrations of TA (0, 1, 10 and 100 µg/mL) were supplemented with a maturation medium and the COCs and subsequent embryonic development were examined. The results showed that 10 µg/mL TA significantly improved the cumulus expansion index (CEI), cumulus-expansion-related genes (PTGS1, PTGS2, PTX-3, TNFAIP6 and HAS2) expression and blastocyst formation rates after parthenogenetic activation (PA), in vitro fertilization (IVF) and somatic cell nuclear transfer (SCNT) compared to the control groups, but not oocyte nuclear maturation. Nevertheless, 10 µg/mL TA dramatically enhanced the mRNA expression of oocyte-development-related genes (BMP15, GDF9, CDC2 and CYCLIN B1), GSH, ATP, SOD1, PGC1α, BMP15, GDF9 and CDC2 levels and reduced intracellular ROS level in porcine oocytes. These results indicated that porcine oocyte cytoplasmic maturation was improved by 10 µg/mL TA treatment during IVM. In contrast, a high concentration of TA (100 µg/mL) significantly decreased the CEI and PTGS1, PTGS2, PTX-3 and HAS2 mRNA expressions in cumulus cells, and reduced oocyte nuclear maturation and the total cell numbers/blastocyst. In general, these data showed that 10 µg/mL TA supplementation has beneficial effects on oocyte cytoplasmic maturation and subsequent embryonic development in pigs.

18.
Acta Pharm Sin B ; 11(9): 2850-2858, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1415197

ABSTRACT

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.

19.
Nat Commun ; 12(1): 250, 2021 01 11.
Article in English | MEDLINE | ID: covidwho-1387324

ABSTRACT

Understanding the mechanism for antibody neutralization of SARS-CoV-2 is critical for the development of effective therapeutics and vaccines. We recently isolated a large number of monoclonal antibodies from SARS-CoV-2 infected individuals. Here we select the top three most potent yet variable neutralizing antibodies for in-depth structural and functional analyses. Crystal structural comparisons reveal differences in the angles of approach to the receptor binding domain (RBD), the size of the buried surface areas, and the key binding residues on the RBD of the viral spike glycoprotein. One antibody, P2C-1F11, most closely mimics binding of receptor ACE2, displays the most potent neutralizing activity in vitro and conferred strong protection against SARS-CoV-2 infection in Ad5-hACE2-sensitized mice. It also occupies the largest binding surface and demonstrates the highest binding affinity to RBD. More interestingly, P2C-1F11 triggers rapid and extensive shedding of S1 from the cell-surface expressed spike glycoprotein, with only minimal such effect by the remaining two antibodies. These results offer a structural and functional basis for potent neutralization via disruption of the very first and critical steps for SARS-CoV-2 cell entry.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal/chemistry , Antibodies, Neutralizing/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/immunology , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Disease Models, Animal , Epitopes , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Protein Binding , Protein Conformation , Receptors, Virus/immunology , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
20.
World J Gastroenterol ; 27(32): 5404-5423, 2021 Aug 28.
Article in English | MEDLINE | ID: covidwho-1379993

ABSTRACT

BACKGROUND: Intestinal barrier breakdown, a frequent complication of intestinal ischemia-reperfusion (I/R) including dysfunction and the structure changes of the intestine, is characterized by a loss of tight junction and enhanced permeability of the intestinal barrier and increased mortality. To develop effective and novel therapeutics is important for the improvement of outcome of patients with intestinal barrier deterioration. Recombinant human angiopoietin-like protein 4 (rhANGPTL4) is reported to protect the blood-brain barrier when administered exogenously, and endogenous ANGPTL4 deficiency deteriorates radiation-induced intestinal injury. AIM: To identify whether rhANGPTL4 may protect intestinal barrier breakdown induced by I/R. METHODS: Intestinal I/R injury was elicited through clamping the superior mesenteric artery for 60 min followed by 240 min reperfusion. Intestinal epithelial (Caco-2) cells and human umbilical vein endothelial cells were challenged by hypoxia/ reoxygenation to mimic I/R in vitro. RESULTS: Indicators including fluorescein isothiocyanate-conjugated dextran (4 kilodaltons; FD-4) clearance, ratio of phosphorylated myosin light chain/total myosin light chain, myosin light chain kinase and loss of zonula occludens-1, claudin-2 and VE-cadherin were significantly increased after intestinal I/R or cell hypoxia/reoxygenation. rhANGPTL4 treatment significantly reversed these indicators, which were associated with inhibiting the inflammatory and oxidative cascade, excessive activation of cellular autophagy and apoptosis and improvement of survival rate. Similar results were observed in vitro when cells were challenged by hypoxia/reoxygenation, whereas rhANGPTL4 reversed the indicators close to normal level in Caco-2 cells and human umbilical vein endothelial cells significantly. CONCLUSION: rhANGPTL4 can function as a protective agent against intestinal injury induced by intestinal I/R and improve survival via maintenance of intestinal barrier structure and functions.


Subject(s)
/pharmacology , Intestines , Reperfusion Injury , Caco-2 Cells , Human Umbilical Vein Endothelial Cells , Humans , Intestinal Mucosa , Recombinant Proteins/pharmacology , Reperfusion Injury/prevention & control
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